4, 6-alpha-pyrone derivatives



Patented July 4, 1950 2,514,325 4,6-ALrHA-PmoNE DERIVATIVES Josef Fried, New Brunswick, N. J., assignor, by mesne assignments, to William R. Warner &

. 00., Inc., New York, N. Y., a corporation of Delaware No Drawing. Application January 9, 1947,

Serial No. 721,149

2 Claims. I

This invention relates to 4,6-a1pha-pyrone derivatives, and to a process'for preparing them.

The novel products of this invention may be represented according to their structural'forinulae as follows; I

, o wherein R. is a member selected from the group consisting of radicals whose structures may be represented as follows:

Phenyl 3,4-dioxymethylene phenyl-land 5,6 A-etio cholenyl on. on;

wherein R1 is a member selected from the group consisting of H, OH and CH3COO radicals.

The new substances are prepared by heating above their melting-points substances having the general formula:

1 formula is an organicradical, ,for' example, alkyl,

aralkyl, aryl, cycloaliphatic and steroid-like radicals. It is desirable to continue the heating until no more carbon dioxide evolves from the reaction chamber.

The initial materials subjected to heat to form the compounds of this invention are themselves novel and form the subject-matter of a copending application, Serial No. 721,148, filed contemporaneously herewith. They are prepared by treating the suitable acyl halides such as benzoyl chloride, piperonylyl chloride. or '3-acet'oxy- A5,6-etiocholenyl chloride with beta-methyl glu taconic anhydride in the presence of-tertia-ry bases, such as pyridine, at low temperatures (from 20 C. to 0 0.). l

The products of this invention are-*useful as intermediates in the preparation of numerous organic chemicals, includes biologically-active-ma terials. They also possess desirable therapeutic properties.

In order more fully to illustrate this invention the following examples aregiven'. All operations were performed in an atmosphere of pure nitrogen and temperatures given are in degrees centigrade. v

EXAMPLEI I y Preparation of 4-methyl-6-phenyZ-alphwpyroae CH; f 3 Y- r I on on' @K/ the refrigerator for 49 hours and then diluted with an equal volume of ice. Thissolutionwas poured with stirring into 30 cc. of concentrated hydrochloric acid containing 40 cc. oficeQ The green precipitate was filtered, washed withjice water and dried. Recrystallization from ethyl acetate gave fat prisms, which melt. at 101 C.- 103 C., and give a purple coloration with ferric chloride in alcohol.

Analysis: Calcdfor C13H1004I C, 67.8; 11.4.4. Found: C, 67.9; H, 4.2.

200 mg. of alpha-benzoyl-betwmethyl glutaconic anhydride prepared as above were heated to 105 C.-1l0 C. and 50 mm. pressure. The melt turned red and carbon dioxide escaped. The temperature was finally raised to 130 C.-140 C. and the evolution of gas subsided after 4 to 5 hours. The masssolidifled on :cooling. 'It'was extracted with ligroine, from which prismatic needles deposited on cooling. Recrystallization from ethyl acetate and pentane gave the pure compound, which melted at 87 C.

Analysis: Calcd for C12HmOz: C, 77.4; H 5.4. Found: C, 77.2; H, 5.1.

The above substance could also be obtainedby refluxing 200 mg. of alpha=benzoyl=beta-methyl glutaconic anhydride with 2 cc. of glacial acetic acid for 2 hours, pouring the solution into :icesodium bicarbonate and recrystallizing the'precipitate as described above.

EXAMPLE II Preparation of 4-methyl-'6-(3,4-diorcy-methylene phenyl) alpha-pyrone Too Solution of "7.6. grams of beta-methyl. glutaconiaanhydride in 30 'cc. of absolute pyridine wasaddeda solution of-piperonylyl chloride (from :grams of piperonylicacid and thionyl chloride) in 20 cc. benzene with stirring andcooling to 1520. ;10 more-cc. 0f gpyridine were added and the'rea t on mixtur w kept .in the refr -.erator-,for .24 hours. ,At the end ,of this period, chloroform was adde dand.the mixture extracted with 50 cc. concentrated hydrochloric acid and ;1,00 grams:of ice. .A good deal of piperonylicacid deposited :during ;this procedure and this was..re-

:movedby filtration. The,chloroform-solutionwas ,sodiumcarbonate. The chloroform solution containing .the neutral products ,was washed with water and evaporated to dryness in vacuo. The

,.dark. red residue was taken up in benzeneand some resinous impuritiesremoved by careful precipitation with pentane. The solution was decanted from the darkcolored residue and evaporatedto small volume. ,,On standing.. overnight .infthe refrigerator, crystals depositedwhich were .fll red and washed withli tle. old enzen T e ,crystals could easily be separated into two fractions, on v ry di fimil ly soluble i be ne-and .m0st-.,o he organic solven and an h one whichr adi y rys a11izedirom benzene r alcoh l. Th diiiicu ySolubl ompound Wasrecrystall zed from al o o t .melted at120s Analysis: Found: .C, 66.32;H,13;56.

The more soluble product .was recrystallized from 95% alcohol with, the aidgoff charcoal, taking care that crystallization did not startbe'fore the .a lphg-pyronyl) ]-A5,6-etiocholene C H: C H: C \C H 2.5 grams ,of..pure, finely powdered 3-acetoxy-n 5,6-etiocholenic acid (M. P. 230-236 .C.) were kept at 0 C. with 10 cc. of pure thionylchloride. At the end of 5 hours the light yellow solution was evaporated to dryness in vacuo. 4 cc. of dry chloroform was added to the crystalline residue and evaporated in order toremove the last traces of trionyl chloride. The crystals melted partially at 158 0., leaving an unmelted residue to as high as 200 vC.

The crystalline ,3-acetoxy-A5,6-etiocholenyl chloride was dissolved in-4 co. chloroform and 940 mg. of beta-methyl glutaconic anhydride were added. To this solution was added 20 cc. of pyridine of -20 C.,and the yellow solution kept at -20 C. for one half hour. While in the refrigerator for the next 44 hours, the solution slowly turned green and deposited some solid material. 30 cc. of concentrated hydrochloric acid and 50 cc. of ice covered With-20D cc. of ether. A solid precipitate formed between the two layers which was removed by filtration. The precipitate consisted of fine platelets which were very difficultly soluble in all common solvents. They were recrystallized from much chloroform, and did not melt up to 265 C. They represent the anhydride of 3-betaacetoxy--A 5,6-etiocholenic acid.

Analysis: C'alcd forCnHezOv: C, 75.2 H, 8.9. Found: C, 74.8; -H;-8.2.

The ethereal layer was extracted once more with dilute hydrochloric acid and then with water until no more blue color went into the aqueous layer. After. drying, the ether solution was brought to small wolume and the alpha (3- acetoxy-(A 5,6-etioch0lenyl) meta-methyl glutaconic anhydride crystallized readily. Altogether 2.3 grams of crystalline product, melting at C. with decomposition, were obtained (70.5% yield).

Recrystallization of this product from ether-pentane yielded rosettes of fine needles. These started to decompose at 146 C. and were completely melted at. around C. When kept for about 5 minutes at C.-l75 0., the melt suddenly crystallized and melted again at 223 C.- 225 C. The substance produced a permanent purple coloration with ferric chloride in alcohol.

Analysis: Calcid for CZBHBGOGI C, 71.8; .H, 7.8. Found: 0,7128; 1 1,726.

2.24 grams of crude alpha-(3-.acetoxy-(A5fietiocholenyl) -'beta-methy1. glutaconic anhydride (M. P. 140 C.) were :heated in a test tube to 140 C. and the temperature was slowly raised to 175 C.-180 C. A vivid evolution of gas occurred and finally the whole mass solidified (35 minutes). The resulting crystalline cake was dissolved in 25 cc. of warm benzene and the red solution poured through a column of 5 grams of Brockmann alumina. The column was eluted with 100 cc. of benzene and the combined light yellow filtrates were evaporated to dryness in vacuo. The residual solid weighed 1.85 grams, which corresponds to 91% of the theory. On recrystallization from alcohol there was obtained 1.35 grams melting at 227 C.228 C. and from the mother liquors another 0.25 gram, melting at 223 C.225 C. This corresponds to a total yield of 78% of the theory. The analytical sample crystallized from alcohol in fine shiny platelets, which melt at 227 C.-229 C. with slight sintering at 223 C.

Analysis: Calcd for C27II3604Z C, 76.4; H, 8.6. Found: C, 76.3; H, 8.5.

EXAMPLE IV Preparation of 3-beta-hydrox'J-17-[6-(4- methyl-alpha-pyronyl) ]-A5,6-etiocholene GE CH =0 I CH3 CH3 6 with water and dried. They were dissolved in cc. of hot benzene and the yellow solution poured through a column containing 3 grams of Brockmann alumina as adsorbent. The column was eluted with 200 cc. of benzene and the combined eluates evaporated to small volume. The 3 beta hydroxy 17 [6 (4 methyl alpha pyronyl) ]-A5,6-etiocholene crystallized in fine feathery needles which melted at 228 C.-231 C., and gave a 35 C. melting point depression when mixed with its acetate. The yield of pure white product was 1.05 grams or 78.5% of the theory.

Analysis: Calcd for C25H3403Z C, 78.5; H, 9.0. Found: C, 78.1; H, 8.5.

The foregoing illustrates the practice of this invention, which however, is not to be limited thereby but is to be construed as broadly as permissible in view of the prior art and limited solely by the appended claims.

I claim:

1. 4 methyl 6 (3,4 dioxymethylene phen yl) alpha pyrone. I

2. The process for preparing 4-methyl-6-(3,4- dioxy methylene phenyl) alpha pyrone, which comprises heating alpha-piperonyl beta-methyl glutaconic anhydride above its melting point but at a temperature below decomposition temperature of the desired product, until evolution of carbon dioxide ceases.

JOSEF FRIED.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,334,180 Elderfield et a1. Nov. 16, 1943 2,362,408 Ruzicka Nov. '7, 1944 2,387,366 Touissant Oct. 23, 1945 OTHER REFERENCES Chemical Abstracts, vol. 25, 21459 (1931). Chemical Abstracts. vol. 22. 240, 241 (1928). 

1. 4-METHYL-6-(3,4-DIOXYMETHYLENE PHENYL) ALPHA PYRONE. 